NO173864B - PROCEDURE FOR THE PREPARATION OF BICYCLIC AMINOCARBOXYL ACIDS, AND INTERMEDIATE PRODUCTS FOR THE PROCEDURE - Google Patents

PROCEDURE FOR THE PREPARATION OF BICYCLIC AMINOCARBOXYL ACIDS, AND INTERMEDIATE PRODUCTS FOR THE PROCEDURE Download PDF

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NO173864B
NO173864B NO88882957A NO882957A NO173864B NO 173864 B NO173864 B NO 173864B NO 88882957 A NO88882957 A NO 88882957A NO 882957 A NO882957 A NO 882957A NO 173864 B NO173864 B NO 173864B
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formula
procedure
compounds
compound
alkanoyl
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Hansjoerg Urbach
Rainer Henning
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Hoechst Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Compounds of the formula I <IMAGE> in which n is 1, 2 or 3, R denotes acyl and R<1> denotes alkyl, cycloalkyl, aralkyl or another carboxyl protecting group are prepared by free-radical cyclisation of compounds of the formula II <IMAGE> in which n, R and R<1> are as defined above and Hal denotes chlorine, bromine or iodine. Intermediates of this process and their use are also described.

Description

Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av bicykliske aminokarboksylsyrer, samt mellomprodukt for fremgangsmåten. The present invention relates to a method for the production of bicyclic aminocarboxylic acids, as well as an intermediate product for the method.

Acylderivater av oktahydroindol-2-karboksylsyre, av okta-hydrocyklopenta[b]pyrrol-2-karboksylsyre, hhv. av decahydro-cyklohepta[b]pyrrol-2-karboksylsyre er eksempelvis kjente fra EP-A-79022, EP-A-50800, EP-A-84164, EP-A-111873, EP-A-37231, US-patent 4 350 704 eller US-patent 4 587 258. Mange av disse forbindelsene viser en bemerkelsesverdig biologisk aktivitet. Eksempelvis hemmer de meget virksomt det angiotensin-omvandlende enzymet eller utmerker seg ved en nootrop virkning. Acyl derivatives of octahydroindole-2-carboxylic acid, of octa-hydrocyclopenta[b]pyrrole-2-carboxylic acid, resp. of decahydro-cyclohepta[b]pyrrole-2-carboxylic acid are for example known from EP-A-79022, EP-A-50800, EP-A-84164, EP-A-111873, EP-A-37231, US patent 4 350,704 or US Patent 4,587,258. Many of these compounds exhibit remarkable biological activity. For example, they very effectively inhibit the angiotensin-converting enzyme or are distinguished by a nootropic effect.

Forbindelser av formel I Compounds of formula I

hvori n = 1-3, R står for hydrogen eller en acylrest og R<1 >står for hydrogen, en forestrende gruppe eller en annen karboksylbeskyttelsesgruppe, spiller en nøkkelrolle ved syntesen av de innledningsvis nevnte acylderivatene. in which n = 1-3, R represents hydrogen or an acyl residue and R<1 > represents hydrogen, an esterifying group or another carboxyl protecting group, plays a key role in the synthesis of the acyl derivatives mentioned at the outset.

Ofte er det fordelaktig når karbonatomet i posisjon 2 på det bicykliske ringsystemet i dette virksomme stoffet oppviser en bestemt absolutt konfigurasjon, fortrinnsvis S-konfigurasjon. Følgelig utgår man ved syntesen fortrinnsvis fra mellomprodukter av formel I som allerede oppviser den ønskede konfigurasjonen på C-2. It is often advantageous when the carbon atom in position 2 of the bicyclic ring system in this active substance exhibits a specific absolute configuration, preferably S-configuration. Consequently, the synthesis preferably starts from intermediate products of formula I which already exhibit the desired configuration at C-2.

Ved noen av de kjente fremstillingsfremgangsmåtene for en forbindelse av formel I var en racematspaltning helt nødvendig dersom man ville oppnå forbindelser med en definert konfigurasjon på C-2. In some of the known preparation methods for a compound of formula I, a racemate cleavage was absolutely necessary if one wanted to obtain compounds with a defined configuration at C-2.

Fra Tetrahedron Letters 1987 1413-1416 er en fremgangsmåte kjent med hvis hjelp man med utgangspunkt i L-asparginsyre i en syntese på totalt 12 trinn når frem til optisk enhetlige oktahydroindol-derivater med en definert konfigurasjon på C-2. From Tetrahedron Letters 1987 1413-1416, a method is known with the help of which starting from L-aspartic acid in a synthesis of a total of 12 steps, optically uniform octahydroindole derivatives with a defined configuration at C-2 are reached.

Det er nå funnet at tilsvarende substituerte serinderivater ved ringslutning kan overføres til optisk enhetlige forbindelser av formel I med den ønskede konfigurasjonen på C-2, uten at det på noe trinn i denne nye fremgangsmåten er nødvendig med en racematspaltning. It has now been found that correspondingly substituted serine derivatives by ring closure can be transferred to optically uniform compounds of formula I with the desired configuration at C-2, without racemate cleavage being necessary at any step in this new process.

Oppfinnelsen vedrører en fremgangsmåte for fremstilling av forbindelser av formel I The invention relates to a method for producing compounds of formula I

hvori in which

n = 1, 2 eller 3 n = 1, 2 or 3

R er ( C^- Cfj )-alkanoyl, (C6-C10 )-aryl-( C^ C^ )-alkanoyl, (C6-Cio)-aroyl, (C^-Cf, )-alkoksykarbonyl eller ( C^- Cn )-aralkoksy-karbonyl, og R is (C 1 -C 10 )-alkanoyl, (C 6 -C 10 )-aryl-(C 1 -C 10 )-alkanoyl, (C 6 -C 10 )-aroyl, (C 1 -C 10 )-alkoxycarbonyl or (C 2 - Cn )-aralkoxycarbonyl, and

R<1> står for (C-L-C4 )-alkyl, eller ( C7- C11 )-aralkyl, R<1> stands for (C-L-C4)-alkyl, or (C7-C11)-aralkyl,

hvor hydrogenatomene ved brohodet-karbonatomene 3a og (5+n)a fortrinnsvis er cis-konfigurerte, som er kjennetegnet ved at man radikalisk ringslutter en forbindelse av formel II where the hydrogen atoms at the bridgehead carbon atoms 3a and (5+n)a are preferably cis-configured, which is characterized by radical ring-closing of a compound of formula II

hvori n, R og R<1> er som definert ovenfor, og Hal står for klor, brom eller jod, i et egnet oppløsningsmiddel ved temperaturer mellom -20°C og 120°C, fortrinnsvis mellom 0°C wherein n, R and R<1> are as defined above, and Hal represents chlorine, bromine or iodine, in a suitable solvent at temperatures between -20°C and 120°C, preferably between 0°C

og kokepunktet for reaksjonsblandingen, eventuelt i nærvær av en radikalinitiator. and the boiling point of the reaction mixture, optionally in the presence of a radical initiator.

Som følgende skjema viser oppnår man ved hjelp av fremgangsmåten ifølge oppfinnelsen med utgangspunkt i eksempelvis 3-bromcyklopenten (V) og L-serin (III) i en syntese som totalt omfatter bare 7 trinn, de optisk enhetlige diastereomerene Ia og Ib, som er homologe med de ovenfor nevnte oktahydroindolderivatene. Når man gjennomfører fremgangsmåten over trinnet med L-serinbenzylesteren reduseres sågar dette trinnantallet med ett trinn til totalt 6 trinn. Karbonatomet i posisjon 2 i det bicykliske ringsystemet for forbindelser av formlene I og II, kan oppvise såvel R- som S-konfigurasjonen; foretrukket er S-konfigurasjonen. As the following diagram shows, the optically uniform diastereomers Ia and Ib, which are homologous, are obtained by means of the method according to the invention starting from, for example, 3-bromocyclopentene (V) and L-serine (III) in a synthesis that comprises a total of only 7 steps with the above-mentioned octahydroindole derivatives. When carrying out the procedure above the step with the L-serine benzyl ester, this number of steps is even reduced by one step to a total of 6 steps. The carbon atom in position 2 in the bicyclic ring system for compounds of formulas I and II can have both the R and S configurations; preferred is the S configuration.

Den radikaliske ringslutningen kan f.eks. gjennomføres med trialkylstannater, som f.eks. med tri-n-butyltinnhydrid i et egnet oppløsningsmiddel mellom -20"C og 120°C, fortrinnsvis mellom 0°C og kokepunktet for reaksjonsblandingen, spesielt ved koketemperaturen, eventuelt i nærvær av en radikalinitiator. Som oppløsningsmiddel kommer derved spesielt aprotiske oppløsningsmidler som benzen, toluen eller xylen på tale. Egnede initiatorer er eksempelvis organiske peroksyder, som tert.-butylperoksyd, substituerte azobisalkansyre-nitriler, som f.eks. 2,2'-azoisosmørsyrenitril (AIBN), merkaptaner og stannater; foretrukket er AIBN. The radical circular conclusion can e.g. is carried out with trialkyl stannates, such as e.g. with tri-n-butyltin hydride in a suitable solvent between -20°C and 120°C, preferably between 0°C and the boiling point of the reaction mixture, especially at the boiling temperature, possibly in the presence of a radical initiator. As a solvent, particularly aprotic solvents such as benzene , toluene or xylene in question. Suitable initiators are, for example, organic peroxides, such as tert-butyl peroxide, substituted azobisalkanoic acid nitriles, such as 2,2'-azisobutyric acid nitrile (AIBN), mercaptans and stannates; AIBN is preferred.

Videre kan den radikaliske ringslutningen gjennomføres i et egnet dipolart, aprotisk oppløsningsmiddel mellom —20°C og kokepunktet for reaksjonsblandingen, fortrinnsvis mellom 10 og 50"C. Egnede dipolare, aprotiske oppløsningsmidler er eksempelvis etere, som dietyleter, tetrahydrofuran og dioksan. Furthermore, the radical ring closure can be carried out in a suitable dipolar, aprotic solvent between -20°C and the boiling point of the reaction mixture, preferably between 10 and 50°C. Suitable dipolar, aprotic solvents are, for example, ethers, such as diethyl ether, tetrahydrofuran and dioxane.

Man fremstiller forbindelsene av formel II med utgangspunkt i cykloalkenylbromider av formel XI, The compounds of formula II are prepared starting from cycloalkenyl bromides of formula XI,

hvori n = 1, 2 eller 3. Disse omsettes med serinderivater av formel IV, hvori R<1> er som definert ovenfor, som metyl eller benzyl og som er R- eller S-, fortrinnsvis S-konfigurerte, i nærvær av en base som K2CO3 i et dipolart, aprotisk opp-løsningsmiddel som acetonitril mellom CC og kokepunktet for in which n = 1, 2 or 3. These are reacted with serine derivatives of formula IV, in which R<1> is as defined above, such as methyl or benzyl and which are R- or S-, preferably S-configured, in the presence of a base as K2CO3 in a dipolar, aprotic solvent such as acetonitrile between CC and the boiling point of

reaksjonsblandingen, fortrinnsvis ved romtemperatur, til forbindelser av formel XII the reaction mixture, preferably at room temperature, to compounds of formula XII

hvori n og R<1> er som angitt ovenfor. wherein n and R<1> are as indicated above.

Idet forbindelsen av formel XII kan foreligge som diastereomerblanding, kan denne adskilles i de rene diastereomerene, evnetuelt via saltdannelser og fraksjonert krystallisasjon, eller ved kromatografi. Dersom de rene diastereomerene anvendes i reaksjonsrekken så bortfaller på et senere trinn diastereomeradskillelsen, hvilket virker fordelaktig inn på det samlede utbyttet. Since the compound of formula XII can exist as a mixture of diastereomers, this can be separated into the pure diastereomers, possibly via salt formation and fractional crystallization, or by chromatography. If the pure diastereomers are used in the reaction series, diastereomer separation is omitted at a later stage, which has a beneficial effect on the overall yield.

Forbindelser av formel XII acyleres så til forbindelser av formel XIII Compounds of formula XII are then acylated to compounds of formula XIII

hvori n, R og R-'- er som definert ovenfor. Acyleringen gjennomføres fortrinnsvis i nærvær av en base i et dipolart, aprotisk oppløsningsmiddel som aceton mellom —20"C og kokepunktet for reaksjonsblandingen, fortrinnsvis ved romtemperatur. Som acyleringsmiddel kommer eksempelvis kloridene av formel RC1 eller anhydridene av formel R2O på tale. Egnede baser er tertiære aminer som trietylamin og uorganiske baser som K2CO3. wherein n, R and R-'- are as defined above. The acylation is preferably carried out in the presence of a base in a dipolar, aprotic solvent such as acetone between -20°C and the boiling point of the reaction mixture, preferably at room temperature. Suitable acylating agents are, for example, the chlorides of formula RC1 or the anhydrides of formula R2O. Suitable bases are tertiary amines such as triethylamine and inorganic bases such as K2CO3.

Omsetningen av forbindelser av formel XIII til forbindelser av formel II, hvori n, R, R<1> og Hal er som definert ovenfor, foregår hensiktsmessig på en slik måte at man erstatter hydroksyfunksjonen for forbindelsene av formel XIII med en avspaltbar gruppe. Følgelig kan det ved kjente fremgangsmåter eksempelvis fremstilles tosylater, mesylater eller triflater, som deretter kan overføres nukleofilt til forbindelser av formel II med klorid, bromid eller jodid. The reaction of compounds of formula XIII to compounds of formula II, in which n, R, R<1> and Hal are as defined above, conveniently takes place in such a way that the hydroxy function of the compounds of formula XIII is replaced by a leaving group. Consequently, for example tosylates, mesylates or triflates can be prepared by known methods, which can then be transferred nucleophilically to compounds of formula II with chloride, bromide or iodide.

Klor kan imidlertid også innføres direkte, f.eks. ved omsetning av forbindelsene av formel XIII med PCI5, brom, f.eks. ved omsetning med PBr3- Jodforbindelsen av formel II fremstilles hensiktsmessig med trifenylfosfin og jod i nærvær av imidazol, fortrinnsvis ved romtemperatur i et aprotisk, upolart oppløsningsmiddel som f.eks. benzen eller toluen fra forbindelser av formel XIII. However, chlorine can also be introduced directly, e.g. by reacting the compounds of formula XIII with PCI5, bromine, e.g. by reaction with PBr3- The iodine compound of formula II is conveniently prepared with triphenylphosphine and iodine in the presence of imidazole, preferably at room temperature in an aprotic, non-polar solvent such as e.g. benzene or toluene from compounds of formula XIII.

Oppfinnelsen vedrører også mellomprodukter kjennetegnet ved at de omfattes av formel II The invention also relates to intermediate products characterized by the fact that they are covered by formula II

hvori in which

n = 1, 2 eller 3, n = 1, 2 or 3,

Hal = klor, brom eller jod, Hal = chlorine, bromine or iodine,

R er ( C-l-Cé, )-alkanoyl, (C6-C10 )-aryl-(C1-C4 )-alkanoyl, (C6-Cig)-aroyl, (C^-C^, )-alkoksykarbonyl eller (C7-<C>11)-<a>ralkoksy-karbonyl, og R is (C-1-C6 )-alkanoyl, (C6-C10 )-aryl-(C1-C4 )-alkanoyl, (C6-C6 )-aroyl, (C6-C6 , )-alkoxycarbonyl or (C7-< C>11)-<a>ralkoxycarbonyl, and

R<1> er ((^-04 )-alkyl, eller ( C7-C1;L )-aralkyl. R<1> is ((C-O4 )-alkyl, or (C7-C1;L )-aralkyl.

De etterfølgende eksemplene tjener til å belyse oppfinnelsen nærmere. The following examples serve to illustrate the invention in more detail.

Eksempel 1 Example 1

N-(2-cyklopenten-l-yl )-L-serinmetylester N-(2-cyclopenten-1-yl)-L-serine methyl ester

Til 24,5 g L-serinmetylesterhydroklorid i 200 ml tørr acetonitril tilsettes 48 g fast K2CO3. Til denne blandingen tilsettes det 23,2 g cyklopentenylbromid i karbontetraklorid ved isavkjøling. Deretter får blandingen nå romtemperatur og det omrøres i 2 timer ved denne temperaturen. Etter avsuging av det faste stoffet inndampes filtratet og resten kromatograferes over kiselgel med CH2CI2 som elueringsmiddel. 48 g of solid K2CO3 are added to 24.5 g of L-serine methyl ester hydrochloride in 200 ml of dry acetonitrile. 23.2 g of cyclopentenyl bromide in carbon tetrachloride are added to this mixture under ice cooling. The mixture is then brought to room temperature and stirred for 2 hours at this temperature. After suctioning off the solid, the filtrate is evaporated and the residue is chromatographed over silica gel with CH2CI2 as eluent.

Utbytte: 7,6 g; frysepunkt 113-126°C Yield: 7.6 g; freezing point 113-126°C

Eksempel 2 Example 2

N-(2-(IS)-cyklopenten-l-yl)-L-serinmetylester N-(2-(1S)-cyclopenten-1-yl)-L-serine methyl ester

Diastereomerblandingen fra eksempel 1 overføres med etanolisk HC1 i eddikester til hydrokloridet (frysepunkt 150-160°C, [a]§° = 10,9° (c = 0,96; CH3OH)) og omkrystalliseres deretter flere ganger fra tørr acetonitril. S,S-forbindelsen (94%, som ECl-salt) har en dreieverdi på [a]§° = -67,5° (c = 0,06; CH3OH); frysepunkt 180°C. The diastereomer mixture from example 1 is transferred with ethanolic HCl in acetic ester to the hydrochloride (freezing point 150-160°C, [a]§° = 10.9° (c = 0.96; CH3OH)) and then recrystallized several times from dry acetonitrile. The S,S compound (94%, as ECl salt) has a rotation value of [a]§° = -67.5° (c = 0.06; CH3OH); freezing point 180°C.

Den frie basen settes fri fra hydrokloridet med vandig K2CO3-oppløsning: The free base is set free from the hydrochloride with aqueous K2CO3 solution:

Eksempel 3 Example 3

N-(2-(IR)-cyklopenten-1-yl)-L-serinmetylester N-(2-(1R)-cyclopenten-1-yl)-L-serine methyl ester

Analogt eksempel 2 oppnås (R,S)-forbindelsen som HCl-salt ved omkrystallisering av hydrokloridet i tørr acetonitril, eddikester og CH2CI2 (ca. 85%). Analogously to example 2, the (R,S) compound is obtained as an HCl salt by recrystallization of the hydrochloride in dry acetonitrile, ethyl acetate and CH2CI2 (approx. 85%).

Frysepunkt 152-154°C; [a]J° = +82,78° (c = 0,61; CH3OH). Freezing point 152-154°C; [α]J° = +82.78° (c = 0.61; CH 3 OH).

[a]g° for den frie basen: +38,3° (c = 0,88; CH3OH) [a]g° for the free base: +38.3° (c = 0.88; CH3OH)

Eksempel 4 Example 4

N-benzyloksykarbonyl-N-(2 - (1E, S)-cyklopenten-l-yl)-L-serinmetylester N-benzyloxycarbonyl-N-(2-(1E,S)-cyclopenten-1-yl)-L-serine methyl ester

10,5 g metylester fra eksempel 1 suspenderes i 164 ml mettet, vandig NaHCC^-oppløsning. For dette formålet tilsettes ved romtemperatur 11,24 ml klormaursyrebenzylester. Etter 2 timers omrøring ekstraheres med eddikester. De organiske fasene vaskes trinnvis med 2N vandig HC1, halvmettet vandig NaHCC>3-oppløsning, vann og mettet vandig NaCl-oppløsning. Etter tørking inndampes blandingen. 10.5 g of the methyl ester from example 1 is suspended in 164 ml of saturated aqueous NaHCO3 solution. For this purpose, 11.24 ml of benzyl chloroformate are added at room temperature. After stirring for 2 hours, extract with vinegar. The organic phases are washed step by step with 2N aqueous HC1, semi-saturated aqueous NaHCl>3 solution, water and saturated aqueous NaCl solution. After drying, the mixture is evaporated.

Resten kromatograferes over kiselgel med CEtøC^/eddikester 95:5. The residue is chromatographed over silica gel with silica gel/acetic acid 95:5.

Eksempel 5 Example 5

2-(S)-[N-benzyloksykarbonyl-N-(2-(IR,S)-cyklopenten-l-yl-amino)]-3-jod-propionsyremetylester 2-(S)-[N-benzyloxycarbonyl-N-(2-(IR,S)-cyclopenten-1-yl-amino)]-3-iodo-propionic acid methyl ester

0,412 g trifenylfosfin og 0,107 g imidazol blandes i 7 ml tørr benzen. For dette formålet tilsettes det dråpevis 0,346 g jod i 3 ml tørr benzen ved romtemperatur. Etter utfelling av gult bunnfall omrøres i 10 minutter. Deretter tilsettes det ved romtemperatur og under lysbeskyttelse dråpevis 0,319 g av alkoholen fra eksempel 4 i 2 ml tørr benzen. Det omrøres i 3 timer ved romtemperatur. Deretter helles blandingen på eter/vann. Eteroppløsningen vaskes med vann, tørkes og innroteres. Resten kromatograferes over kiselgel med cykloheksan/eddikester 9:1. 0.412 g of triphenylphosphine and 0.107 g of imidazole are mixed in 7 ml of dry benzene. For this purpose, 0.346 g of iodine is added dropwise in 3 ml of dry benzene at room temperature. After precipitation of a yellow precipitate, stir for 10 minutes. Then, at room temperature and under protection from light, 0.319 g of the alcohol from example 4 is added dropwise in 2 ml of dry benzene. It is stirred for 3 hours at room temperature. The mixture is then poured onto ether/water. The ether solution is washed with water, dried and centrifuged. The residue is chromatographed over silica gel with cyclohexane/acetic ester 9:1.

Utbytte: 0,2 g olje; Rf: 0,65 (Si02; CH2Cl2/eddikester 95:5; I2) Yield: 0.2 g of oil; Rf: 0.65 (SiO 2 ; CH 2 Cl 2 /acetic ester 95:5; I 2 )

Eksempel 6 Example 6

N-benzy loksykarbonyl-(IS,3S,5S)-2-azabicyklo[3.3.0]-oktan-3-karboksylsyremetylester og N-benzyloksykarbonyl-(lR,3S,5R)-2-azabicyklo-[3.3.0]-oktan-3-karboksyl syrernetylester N-benzyloxycarbonyl-(1R,3S,5S)-2-azabicyclo[3.3.0]-octane-3-carboxylic acid methyl ester and N-benzyloxycarbonyl-(1R,3S,5R)-2-azabicyclo[3.3.0]- octane-3-carboxylic acid ethyl ester

3,25 g jodforbindelse fra eksempel 5, 521 mg azobisisobutyro-nitril (AIBN) og 2,31 g tri-n-butyltinnhydrid oppløses i 260 ml tørr benzen. Det kokes i 4 timer under tilbakeløp under nitrogen. Deretter inndampes og resten opptas i eter. Eteroppløsningen omrøres i 30 minutter med 10% vandig KF-oppløsning; etter filtrering tørkes eteroppløsningen og inndampes. 3.25 g of the iodine compound from example 5, 521 mg of azobisisobutyronitrile (AIBN) and 2.31 g of tri-n-butyltin hydride are dissolved in 260 ml of dry benzene. It is boiled for 4 hours under reflux under nitrogen. It is then evaporated and the residue taken up in ether. The ether solution is stirred for 30 minutes with 10% aqueous KF solution; after filtration, the ether solution is dried and evaporated.

Resten kromatograferes over kiselgel med cykloheksan/- eddikester 4:1. The residue is chromatographed over silica gel with cyclohexane/acetic ester 4:1.

Eksempel 7 N-benzyloksykarbonyl-(IR,3S,5R)-2-azabi cyklo-[3.3.0]-oktan-3-karboksylsyremetylester 1 g diastereomerblanding fra eksempel 6 oppløses i 10 ml benzylalkohol, 0,35 ml titantetraisopropylat tilsettes dråpevis og det omrøres i oljepumpevakuum i 4 timer ved 90°C. Deretter tilsettes det dråpevis ytterligere 1,6 ml titantetraisopropylat og det omrøres i 6 timer ved 90° i oljepumpevakuum. Deretter fjernes benzylalkoholen i vakuum og resten opptas i eter, eteren vaskes med 2N vandig HC1, deretter med mettet, vandig NaHC03-oppløsning og etter frasugning av bunnfallet med mettet, vandig NaCl-oppløsning. Etter tørking blir det inndampet. Resten kromatograferes over kiselgel med cykloheksan/eddikester 9:1. Det først eluerte produktet er (lR,3S,5R)-forbindelsen (cis, ekso-konfigurasjon). Example 7 N-benzyloxycarbonyl-(IR,3S,5R)-2-azabi cyclo-[3.3.0]-octane-3-carboxylic acid methyl ester 1 g of diastereomer mixture from example 6 is dissolved in 10 ml of benzyl alcohol, 0.35 ml of titanium tetraisopropylate is added dropwise and it is stirred in an oil pump vacuum for 4 hours at 90°C. A further 1.6 ml of titanium tetraisopropylate is then added dropwise and it is stirred for 6 hours at 90° in an oil pump vacuum. The benzyl alcohol is then removed in vacuo and the residue is taken up in ether, the ether is washed with 2N aqueous HCl, then with saturated aqueous NaHCO 3 solution and after suctioning off the precipitate with saturated aqueous NaCl solution. After drying, it is evaporated. The residue is chromatographed over silica gel with cyclohexane/acetic ester 9:1. The first eluted product is the (1R,3S,5R) compound (cis, exo configuration).

Eksempel 8 Example 8

N-benzyloksykarbonyl-(1R,3S,5R )-2-azabicyklo-[3.3.0]-oktan-3-karboksylsyrernetylester N-Benzyloxycarbonyl-(1R,3S,5R)-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid methyl ester

Det produktet som elueres etter cis,ekso-forbindelsen fra eksempel 7 er (IS,3S,5S)-forbindelsen (cis,endo-konfigurasjon). The product eluted after the cis,exo compound from Example 7 is the (IS,3S,5S) compound (cis,endo configuration).

Utbytte: 553 mg olje (fra blandingen i eksempel 7). Yield: 553 mg of oil (from the mixture in Example 7).

Eksempel 9 Example 9

(IR,3S,5R)-2-azabicyklo-[3.3.0]-oktan-3-karboksylsyre (IR,3S,5R)-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid

400 mg av sluttproduktet fra eksempel 7 oppløses i 10 ml etanol, dertil tilsettes 50 mg Pd/C (10%) og det dehydreres i 6 timer. 400 mg of the final product from example 7 is dissolved in 10 ml of ethanol, 50 mg of Pd/C (10%) is added thereto and it is dehydrated for 6 hours.

Etter frasugning av katalysatoren inndampes det og resten utrøres med eddikester. After suctioning off the catalyst, it is evaporated and the residue is stirred with vinegar.

Utbytte: 90 mg; frysepunkt 220-225°C. Yield: 90 mg; freezing point 220-225°C.

Eksempel 10 Example 10

(IS,3S,5S)-2-azabicyklo-[3.3.0]-oktan-3-karboksylsyre (IS,3S,5S)-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid

Analogt eksempel 9 omsettes 500 mg fra eksempel 8. Utbytte: 186 mg; frysepunkt 235-238°C. Analogously to example 9, 500 mg from example 8 is reacted. Yield: 186 mg; freezing point 235-238°C.

Claims (2)

1. Fremgangsmåte for fremstilling av en forbindelse av formel I hvori n = 1, 2 eller 3 R er (C1-C6 )-alkanoyl, (C6-C10)-aryl-(C1-C4)-alkanoyl, (C6-C^o )-aroyl, (C^-C^, )-alkoksykarbonyl eller (C7-Cn )-aralkoksy-karbonyl, og R<1> står for (C1-C4 )-alkyl, eller (C7-.Cn )-aralkyl hvor hydrogenatomene ved brohodet-karbonatomene 3a og (J5+n)a fortrinnsvis er cis-konfigurerte, karakterisert ved at man radikalisk ringslutter en forbindelse av formel II hvori n, R og R<1> er som definert ovenfor, og Hal står for klor, brom eller jod, i et egnet oppløsningsmiddel ved temperaturer mellom -20°C og 120°C, fortrinnsvis mellom 0°C og kokepunktet for reaksjonsblandingen, eventuelt i nærvær av en radikalinitiator.1. Process for the preparation of a compound of formula I in which n = 1, 2 or 3 R is (C 1 -C 6 )-alkanoyl, (C 6 -C 10 )-aryl-(C 1 -C 4 )-alkanoyl, (C 6 -C 6 Cn )-aralkoxycarbonyl, and R<1> stands for (C1-C4 )-alkyl, or (C7-.Cn )-aralkyl where the hydrogen atoms at the bridgehead carbon atoms 3a and (J5+n)a are preferably cis-configured, characterized by radical ring closure of a compound of formula II wherein n, R and R<1> are as defined above, and Hal represents chlorine, bromine or iodine, in a suitable solvent at temperatures between -20°C and 120°C, preferably between 0°C and the boiling point of the reaction mixture, possibly in the presence of a radical initiator. 2. Forbindelse, karakterisert ved at den omfattes av formel II, hvori n = 1, 2 eller 3, Hal = klor, brom eller jod, R er (C-l-C^, )-alkanoyl, ( C6-C10 )-aryl-( C^ C^ )-alkanoyl, (C6-Cio)-aroyl, (cl_c6)-alkoksykarbonyl eller ( C^- Cn)-aralkoksy-karbonyl, og R<1> er (C1-C4 )-alkyl, eller ( C^- C^ )-aralkyl.2. Compound, characterized in that it is covered by formula II, in which n = 1, 2 or 3, Hal = chlorine, bromine or iodine, R is (C 1 -C 1 , )-alkanoyl, (C 6 -C 10 )-aryl-(C 1 -C 2 )-alkanoyl, (C 6 -C 10 )-aroyl, (C 1 -C 6 )-alkoxycarbonyl or (C 1 -C 6 )-araloxy- carbonyl, and R<1> is (C1-C4 )-alkyl, or (C1-C4 )-aralkyl.
NO882957A 1987-07-03 1988-07-01 Process for Preparation of Bicyclic Aminocarboxylic Acids, and Intermediate of the Process NO173864C (en)

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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3839127A1 (en) * 1988-11-19 1990-05-23 Hoechst Ag PYRROLIDONE-2-CARBONIC ACID DERIVATIVES WITH PSYCHOTROPER EFFECT
US5952497A (en) * 1996-07-10 1999-09-14 University Of Georgia Research Foundation N.sup.α -Bpoc amino acid pentafluorophenyl (Pfp) esters and 3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl (ODhbt) esters
CA2586547A1 (en) * 2004-11-05 2006-05-11 King Pharmaceuticals Research & Development, Inc. Stabilized individually coated ramipril particles, compositions and methods

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5572169A (en) * 1978-11-27 1980-05-30 Tanabe Seiyaku Co Ltd Isoquinoline derivative and its preparation
IL58849A (en) * 1978-12-11 1983-03-31 Merck & Co Inc Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them
US4294832A (en) * 1979-04-28 1981-10-13 Tanabe Seiyaku Co., Ltd. Tetrahydroisoquinoline compounds and a pharmaceutical composition thereof
FR2491469A1 (en) * 1980-10-02 1982-04-09 Science Union & Cie 2-Carboxy-per:hydro-indole(s) and per or tetra:hydro-isoquinoline(s) - having a carboxy-substd. amino-acyl N-gp., inhibit carboxy:poly:peptidase(s), and kininase II and control hypertension
FR2503155A2 (en) * 1980-10-02 1982-10-08 Science Union & Cie NOVEL SUBSTITUTED IMINO DIACIDES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS AN ENZYME INHIBITOR
US4508729A (en) * 1979-12-07 1985-04-02 Adir Substituted iminodiacids, their preparation and pharmaceutical compositions containing them
IE52663B1 (en) * 1980-04-02 1988-01-20 Warner Lambert Co Substituted acyl derivatives of octahydro-1h-indole-2-carboxylic acids
DE3177311D1 (en) * 1980-08-30 1994-06-09 Hoechst Ag Amino acid derivatives, processes for their preparation, compositions containing them and their use.
IL63813A0 (en) * 1980-09-17 1981-12-31 Univ Miami Carboxyalkyl peptides and thioethers and ethers of peptides,antihypertensive compositions and methods for their use
ZA817261B (en) * 1980-10-23 1982-09-29 Schering Corp Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them
DE19575012I2 (en) * 1980-10-23 2002-01-24 Schering Corp Carboxyalkyl dipeptides Process for their preparation and medicaments containing them
US4374847A (en) * 1980-10-27 1983-02-22 Ciba-Geigy Corporation 1-Carboxyalkanoylindoline-2-carboxylic acids
GB2086390B (en) * 1980-11-03 1984-06-06 Ciba Geigy Ag 1-carboxy-azaalkanoylindoline-2-carboxylic acids process for their manufacture pharmaceutical preparations containing these compounds and their therapeutic application
US4820729A (en) * 1981-03-30 1989-04-11 Rorer Pharmaceutical Corporation N-substituted-amido-amino acids
DE3226768A1 (en) * 1981-11-05 1983-05-26 Hoechst Ag, 6230 Frankfurt DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (3.3.0) -OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF
GR78413B (en) * 1981-12-29 1984-09-27 Hoechst Ag
DE3210496A1 (en) * 1982-03-23 1983-10-06 Hoechst Ag NEW DERIVATIVES OF BICYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF, AND NEW BICYCLIC AMINO ACIDS AS INTERMEDIATE STAGES AND METHOD FOR THE PRODUCTION THEREOF
DE3211397A1 (en) * 1982-03-27 1983-11-10 Hoechst Ag, 6230 Frankfurt SPIRO (4. (3 + N)) - 2-AZA-3-CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THEIR USE
DE3211676A1 (en) * 1982-03-30 1983-10-06 Hoechst Ag NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF AND NEW CYCLOALKA (C) PYRROL CARBONIC ACIDS AS THE INTERMEDIATE LEVELS AND METHODS
DE3242151A1 (en) * 1982-11-13 1984-05-17 Hoechst Ag, 6230 Frankfurt NEW DERIVATIVES OF TRICYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF, AND NEW BICYCLIC AMINO ACIDS AS INTERMEDIATE STAGES AND METHOD FOR THE PRODUCTION THEREOF
DE3246503A1 (en) * 1982-12-16 1984-06-20 Hoechst Ag, 6230 Frankfurt DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (5.3.0) -DECAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THESE AGENTS AND THE USE THEREOF
DE3300316A1 (en) * 1983-01-07 1984-07-12 Hoechst Ag, 6230 Frankfurt DISUBSTITUTED PROLIN DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE
DE3300774A1 (en) * 1983-01-12 1984-07-12 Hoechst Ag, 6230 Frankfurt NEW SPIROCYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF AND NEW SPIROCYCLIC AMINO ACIDS AS INTERMEDIATE PRODUCTS AND METHOD FOR THE PRODUCTION THEREOF
DE3303112A1 (en) * 1983-01-31 1984-08-09 Hoechst Ag, 6230 Frankfurt METHOD FOR RACEMATE SEPARATION OF OPTICALLY ACTIVE BICYCLIC IMINO (ALPHA) CARBONIC ACIDS
DE3315464A1 (en) * 1983-04-28 1984-10-31 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS
DE3322530A1 (en) * 1983-06-23 1985-01-10 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING MONO, BI AND TRICYCLIC AMINO ACIDS
DE3324263A1 (en) * 1983-07-06 1985-01-17 Hoechst Ag, 6230 Frankfurt DERIVATIVES OF 2-AZABICYCLO (3.1.0) HEXAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF, AND 2-AZABICYCLO (3.1.0) HEXANE DERIVATIVES AS INTERMEDIATE PRODUCTS AND PROCESS PRODUCTS
DE3345355A1 (en) * 1983-12-15 1985-06-27 Hoechst Ag, 6230 Frankfurt METHOD FOR RACEMATE CLEAVING BICYCLIC IMINO (ALPHA) CARBONIC ACID ESTERS
AU581919B2 (en) * 1984-07-30 1989-03-09 Schering Corporation Process for the preparation of cis, endooctahydrocyclopenta (b) pyrrole-2-carboxylate
DE3431541A1 (en) * 1984-08-28 1986-03-06 Hoechst Ag, 6230 Frankfurt CIS, ENDO-2-AZABICYCLOALKAN-3-CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND INTERMEDIATE PRODUCTS IN THEIR PRODUCTION
US4783537A (en) * 1985-11-13 1988-11-08 Pennwalt Corporation α-(aminoalkyl)-arylacetic acid derivatives
GB8716278D0 (en) * 1987-07-10 1987-08-19 Fujisawa Pharmaceutical Co Antimicrobial agent
US4922083A (en) * 1988-04-22 1990-05-01 Thermon Manufacturing Company Flexible, elongated positive temperature coefficient heating assembly and method

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